1. Field of the Invention
The present invention relates to pest controlling compositions formed by mixing a first compound having pest controlling activity together with a second compound capable of inhibiting a phosphodiesterase enzyme of the pest. The invention also relates to methods of controlling pests by treatment with the aforementioned compositions.
2. Description of the Background Art
Despite the recent development and great promise of such advanced pest controlling compositions as chemical sterilants, pheromones or ecologically-based insect control strategies, it is doubtless that, at present, the use of chemical pesticides still plays a predominant role. The use of insecticides often represents the difference between profitable crop production for farmers and no marketable crop at all, and the value of insecticides in controlling human and animal diseases has been dramatic.
Therefore, in parallel to the aforementioned newer technologies for pest control, there has been active research and investigation into the detailed biochemical modes of action of existing known chemical pesticides. Thus, for example, Nathanson et al., Molecular Pharmacology 20:68-75 (1981) presented evidence indicating that the formamidine pesticides chlordimeform (CDM) and N-demethylchlordimeform (DCDM) may affect octopaminergic neurotransmission. CDM and DCDM have been reported to mimic the effects of octopamine in stimulating light emission in the firefly lantern (Hollingworth, R. M. et al., Science, 208:74-76 (1980)), and in effecting nerve-evoked muscle responses in the locust leg (Evans, P.D., Nature, 287:60-62 (1980)). Nathanson et al., supra, found that DCDM, which is the probable in vivo metabolite of CDM, is about six-fold more potent than octopamine itself as a partial agonist of light organ octopamine-stimulated adenylate cyclase. Stimulation by the formamidines resulted in increased formation of the intracellular messenger, cyclic AMP. This stimulation was blocked by cyproheptadine, clozapine, fluphenazine and phentolamine compounds, also known to block the octopamine receptor. Nathanson et al. concluded that DCDM is the most potent octopaminergic compound described.
Similar results were observed by Hollingworth et al. (reported in the Scientific Papers of the Institute of Organic and Physical Chemistry of Wroclaw Technical University, No. 22, Conference 7 (1980)). These authors demonstrated that certain formamidines act on octopamine receptors to induce the synthesis of cyclic AMP, and that this response is blocked by both phentolamine and cyproheptadine, which are known to act as octopaminergic antagonists in insects. The authors also suggested that these formamidines are potent stimulators of the octopamine sensitive adenylate cyclases in the thoracic ganglia of Periplaneta americana, and in the ventral nerve cord and fat body of M. sexta. The authors suggest that the stimulation of octopamine receptors underlies a number of toxic responses seen with formamidines on insects.
It should be noted that the presence of an insect adenylate cyclase enzyme which is sensitive to octopamine as a "neuro transmitter" has been known for some time (Nathanson et al, Science, 180:308-310 (1973) (cockroach); Nathanson, ibid: 203: 65-68 (1979) (firefly); Evans, J., Neurochem, 30:1015-1022 (1978) (cockroach)).
The study of cyclic AMP (cAMP) as a "second messenger" has led to the accepted model that a hormone or neurotransmitter binds at a cell-membrane bound receptor, which activates adenylate cyclase to a form capable of converting ATP in the cytoplasm of the cell into cAMP. cAMP then relays the signal brought by the hormone or neurotransmitter from the membrane to the interior of the cell. Agonists of the hormone or neurotransmitter are, by definition, capable of eliciting the same response (see, for example, Nathanson and Greengard, Scientific American, 237:108-119 (1977)). Once formed inside the cell, cyclic AMP presumably binds to a protein kinase which is then capable of phosphorylating appropriate proteins, etc.
Given the continuous need for increased selectivity and effectiveness in pest control agents, it became desirable that the greater understanding of the biochemical mode of action of the formamidines be utilizable in some manner to improve their effectiveness, and to lead to a general rational formulation of pest control agents.